Prior to World War II, 80% of individuals with spinal cord injury (SCI) died within 3 years of the injury primarily due to kidney and pulmonary infections, pressure sores and depression. However, with the advent of antibiotic drugs and advancements in acute care and rehabilitation, the life expectancy of individuals with SCI has increased to near that for able-bodied individuals. However, cardiovascular disease is now a leading cause of death and morbidity for individuals with SCI. {In fact, morbidity and mortality from cardiovascular disease in individuals with chronic SCI exceeds that caused by renal and pulmonary complications, the primary cause of mortality in previous decades.} The risk for significant cardiovascular dysfunction is aggravated by the sedentary lifestyle of the typical individual with SCI. Specifically, individuals with SCI are placed at the lowest end of the human fitness spectrum. Therefore, exercise with the arms is often recommended for individuals with SCI, based on studies demonstrating improvements in aerobic capacity and lipoprotein profiles. The Centers for Disease Control has recommended further research to evaluate the efficacy of exercise to prevent the development of cardiovascular disease in individuals with SCI. {Understanding the mechanisms responsible for the increased susceptibility to cardiovascular disease as well as therapeutic interventions has the potential to impact the lives of millions of individuals and families with spinal cord injury. Therefore, we will test the hypothesis that mid-thoracic spinal cord injury increases cardiac nerve growth factor (NGF) content. The increased cardiac NGF content causes cardiac sympathetic-hyper-innervation. Specifically, the increased cardiac NGF content increases morphometric parameters (maximal diameter, cross- sectional area, density and dendritic arborization) of individual cardiac projecting sympathetic preganglionic neurons (SPNs), and postganglionic sympathetic neurons located within the stellate ganglion as well as increased cardiac sympathetic innervation density. This cardiac sympathetic-hyper-innervation, "cardiac rewiring", alters cardiac physiology and increases the susceptibility to ventricular arrhythmias. Furthermore, intra-pericardial infusion of an anti-NGF antibody, in T5 spinal cord transected rats, reduces cardiac sympathetic-hyper-innervation and reduces the susceptibility to ventricular arrhythmias. Similarly, daily exercise also reduces cardiac NGF content, reduces cardiac sympathetic-hyper-innervation and decreases the susceptibility to ventricular arrhythmias. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is now a leading cause of death and morbidity for individuals with spinal cord injury. In fact, morbidity and mortality from cardiovascular disease in individuals with chronic spinal cord injury exceeds that caused by renal and pulmonary complications, the primary cause of mortality in previous decades. We will investigate the mechanisms mediating the increased risk.